Do Parenterals have to be 100% free of Particles?

Parenterals must be 100% visually inspected in accordance with pharmacopoeia specifications. This involves checking not only for damage to the primary container, but also for the absence of particles. But do these medicines really have to be 100% free of particles?

In principle, yes, but this freedom from particles only applies to visible particles. Small, so-called sub-visible particles may be present according to the pharmacopoeia specifications. For example, the European Pharmacopoeia allows up to 25 particles (<= 10 µm) per mL and up to 3 particles (<= 25 µm) in containers up to 100 mL using the light obscuration counting method.

It is important to distinguish between intrinsic and extrinsic particles. Intrinsic particles, which originate from the medicinal product or active substance itself, are usually undesirable, but can also be part of the medicinal product and described in the marketing authorisation, as is the case with suspensions. Extrinsic particles, such as fibres, glass or abrasion from machine parts, on the other hand, are always undesirable. The sterile, liquid medicine should be free of these particles.

Technically, however, it is not possible to produce a drug completely free of particles. A 100% particle-free batch is therefore not feasible, and units with particles must be sorted out. This is done as part of the prescribed 100% visual inspection during production.

However, the particle inspection itself is also problematic. Although every container in a batch is visually inspected for visible particles, this inspection is probabilistic. This means that the probability of detecting visible particles is not 100%. Regardless of whether the inspection is carried out manually or using a fully automated visual inspection machine (AVI), not all units with particles are recognised. The probability of detection depends on many factors, such as the size, colour, opalescence and shape of the particle as well as its position in the container. The packaging material also plays a role in the probability of detection. Opaque plastic packaging (e.g. BFS) or amber glass play a role here.

In summary, it can be said that batch-wise production without particles is not possible and not all units with particles are reliably recognised. How does this fit in with the requirement that sterile medicinal products for injection should be free of particles?

A closer look at the pharmacopoeia will help here. The requirement is not 'free from particles', but 'practically/essentially free from visible foreign particles'. This difficult-to-measure term was clarified in 2014 in the USP chapter <790> Visible Particulates in Injections. It describes an AQL test which, if passed with an AQL of 0.65 or better, defines a batch as practically free of particles. In practice, this means that after a validated 100% visual inspection of all units in a batch, during which all recognised particles are sorted out, a random sample is re-inspected in accordance with the AQL inspection plan. The permitted number of units with particles depends on the batch size. This test is not mandatory in Europe, but is understood to be state of the art and is carried out in most pharmaceutical companies. The ECA Visual Inspection Group's Best Practice Guide also suggests this approach. Of course, other ways of improving the quality of visual inspection are also conceivable, such as a general second 100% inspection of all batches. This is already practised by many companies, but only for batches intended for the Japanese market.